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United States Patent |
5,589,156
|
Henry
|
December 31, 1996
|
Prilocaine and hydrofluourocarbon aerosol preparations
Abstract
Aerosol compositions used for anesthetizing mammals in both human and
veterinary applications include prilocaine base solubilized in the
hydrofluorocarbon (HFC) propellants 1,1,1,2-tetrafluoroethane and
1,1,1,2,3,3,3-heptafluoropropane. Prilocaine base has been found to be
readily soluble in HFC propellants when combined in liquid or micro rod
form, and a solution stable to temperatures as low as -82.degree. C. is
formed upon combination of the two components. In the aerosol
compositions, the HFCs are the only propellants used. Additional
pharmaceutical constituents can also be combined the the prilocaine
base/HFC composition to provide a multi-component anesthetic, and it has
been found that the presence of prilocaine in the combination can assist
in solubilizing and/or suspending these pharmaceutical consituents. Some
example pharmaceutical compositions within the practice of this invention
include HFC, prilocaine base, and a pharmaceutical other prilocaine
selected from the group consisting of bronchodilators, antiinflammatories,
antitusives, vasoactive drugs, vasoconstrictors, antibiotics, peptides,
steroids, enzymes, antihistamines, hormones, enzyme and receptor
inhibitors and agonists, 5-aminolevulinic acid, antiseptics,
disinfectants, procaine, cocaine, chloroprocaine, tetractaine,
mepivacaine, lidocaine, bupivacaine, etidocaine, ropivacaine, benzocaine,
and phenylephrine.
Inventors:
|
Henry; Richard A. (7 Toronto Street, Kingston, Ontario, CA)
|
Appl. No.:
|
435812 |
Filed:
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May 5, 1995 |
Current U.S. Class: |
424/45; 424/46; 424/47; 514/818; 514/974 |
Intern'l Class: |
A61K 009/12 |
Field of Search: |
424/45,47,46
514/818,974
|
References Cited
U.S. Patent Documents
5118494 | Jun., 1992 | Schultz et al. | 424/45.
|
5190029 | Mar., 1993 | Byron et al. | 424/45.
|
5225183 | Jun., 1993 | Purewal et al. | 424/45.
|
5276032 | Jan., 1994 | King et al. | 514/239.
|
5380754 | Jan., 1995 | Miller et al. | 514/513.
|
Foreign Patent Documents |
07333 | Jul., 1990 | WO | 424/45.
|
14466 | Sep., 1992 | WO | 424/45.
|
Other References
Mor en, F. et al. (1993). Aerosols in Medicine. Principles, Diagnosis and
Therapy. Elsevier Sci. Publishers, pp. 303-319.
Madar, M. J. (1993). J. Appl. Physiology 74(3): 1419-1424.
"Neural blockade in Clinical Anesthesia and Management of Pain" 2nd
Edition. Chapters 1 and 2. Edited by Michael J. Cousins and Phillip O.
Bridenbaugh. Published by Lippencott. (1989).
|
Primary Examiner: Bawa; Raj
Attorney, Agent or Firm: Whitham, Curtis, Whitham & McGinn
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation-in-part application of the co-pending
patent application filed Mar. 24, 1995, having U.S. Ser. No. 08/408,877,
and the patent application filed May 2, 1994, having U.S. Ser. No.
08/236,408, now U.S. Pat. No. 5,453,445, and the co-pending patent
application filed Mar. 17, 1995, having U.S. Ser. No. 08/405,930, and the
complete contents of these three patent applications are herein
incorporated by reference.
Claims
We claim:
1. An aerosol composition for delivering topical local anesthetic to a
mammal, comprising:
1-99% wt of hydrofluorocarbon propellant selected from the group consisting
of 1,1,1,2-tetrafluoroethane and 1,1,1,2,3,3,3-heptafluoropropane and
combinations thereof, said hydrofluorocarbon propellant being the sole
propellant in said aerosol composition;
1-99% wt prilocaine base solubilized within said hydrofluorocarbon
propellant, said prilocaine base and said hydrofluorocarbon propellant
forming a solution that is stable at reduced temperature of at least
-82.degree. C.; and
0.01-99% wt of a pharmaceutical other than prilocaine solubilized in said
hydrofluorocarbon propellant selected from the group consisting of
bronchodilators, antiinflammatories, antitusives, vasoactive drugs,
vasoconstrictors, antibiotics which are not antiseptics, peptides which
are not enzymes, steroids, enzymes, antihistamines, hormones,
5-aminolevulinic acid, antiseptics, disinfectants, procaine, cocaine,
chloroprocaine, tetracaine, mepivacaine, lidocaine, bupivacaine,
etidocaine, ropivacaine, benzocaine, and phenylephrine.
2. An aerosol composition for delivering topical local anesthetic to a
mammal, comprising:
1-99% wt of hydrofluorocarbon propellant selected from the group consisting
of 1,1,1,2-tetrafluoroethane and 1,1,1,2,3,3,3-heptafluoropropane and
combinations thereof, said hydrofluorocarbon propellant being the sole
propellant in said aerosol composition;
1-99% wt prilocaine base solubilized within said hydrofluorocarbon
propellant, said prilocaine base and said hydrofluorocarbon propellant
forming a solution that is stable at reduced temperature of at least
-82.degree. C.
3. A method of solubilizing or suspending medicaments in hydrofluorocarbon
propellants to form an aerosol composition for delivery to a mammal,
comprising the steps of:
dissolving 1-99 wt % prilocaine base in 1-99% wt of a hydrofluorocarbon
propellant selected from the group consisting of 1,1,1,2-tetrafluoroethane
and 1,1,1,2,3,3,3-heptafluoropropane, and combinations thereof, to produce
a solution of prilocaine base and hydrofluorocarbon propellant that is
stable at a reduced temperature of at least -82.degree. C., said
hydrofluorocarbon propellant being the sole propellant in said aerosol
composition; and
incorporating 0.01-99wt % of a medicament other than prilocaine selected
from the group consisting of bronchodilators, antiinflammatories,
antitusives, vasoactive drugs, vasoconstrictors, antibiotics which are not
antiseptics, peptides which are not enzymes, steroids, enzymes,
antihistamines, hormones, 5-aminolevulinic acid, antiseptics,
disinfectants, procaine, cocaine, chloroprocaine, tetracaine, mepivacaine,
lidocaine, bupivacaine, etidocaine, ropivacaine, benzocaine, and
phenylephrine into said solution by a method selected from the group
consisting of solubilizing and suspending.
4. The method of claim 3 wherein said dissolving and incorporating steps
are performed simultaneously.
5. The aerosol composition of claim 1 wherein said pharmaceutical is a
bronchodilator.
6. The aerosol composition of claim 1 wherein said pharmaceutical is an
antiinflammatory.
7. The aerosol composition of claim 1 wherein said pharmaceutical is an
antitusive.
8. The aerosol composition of claim 1 wherein said pharmaceutical is
selected from the group consisting of vasoactive drugs and
vasoconstrictors.
9. The aerosol composition of claim 1 wherein said pharmaceutical is an
antibiotic.
10. The aerosol composition of claim 1 wherein said pharmaceutical is a
peptide.
11. The aerosol composition of claim 1 wherein said pharmaceutical is a
steroid.
12. The aerosol composition of claim 1 wherein said pharmaceutical is an
enzyme.
13. The aerosol composition of claim 1 wherein said pharmaceutical is an
antihistamine.
14. The aerosol composition of claim 1 wherein said pharmaceutical is a
hormone.
15. The aerosol composition of claim 1 wherein said pharmaceutical is
selected from the group consisting of enzyme and receptor inhibitors and
agonists.
16. The aerosol composition of claim 1 wherein said pharmaceutical is
5-aminolevulinic acid.
17. The aerosol composition of claim 1 wherein said pharmaceutical is an
antiseptic.
18. The aerosol composition of claim 1 wherein said pharmaceutical is a
disinfectant.
19. The aerosol composition of claim 1 wherein said pharmaceutical is
procaine.
20. The aerosol composition of claim 1 wherein said pharmaceutical is
cocaine.
21. The aerosol composition of claim 1 wherein said pharmaceutical is
chloroprocaine.
22. The aerosol composition of claim 1 wherein said pharmaceutical is
tetracaine.
23. The aerosol composition of claim 1 wherein said pharmaceutical is
mepivacaine.
24. The aerosol composition of claim 1 wherein said pharmaceutical is
lidocaine.
25. The aerosol composition of claim 1 wherein said pharmaceutical is
bupivacaine.
26. The aerosol composition of claim 1 wherein said pharmaceutical is
etidocaine.
27. The aerosol composition of claim 1 wherein said pharmaceutical is
ropivacaine.
28. The aerosol composition of claim 1 wherein said pharmaceutical is
benzocaine.
29. The aerosol composition of claim 1 wherein said pharmaceutical is
phenylephrine.
Description
DESCRIPTION
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention is generally related to aerosol formulations which include
hydrofluoride propellants and prilocaine base.
2. Description of the Prior Art
Prilocaine is a local anesthetic drug which has the chemical formula:
##STR1##
Prilocaine is described in British Patent 839,943 (1960 to Astra), and
takes the form of crystalline needles having a melting point of
37.degree.-38.degree. C. The hydrochloride salt, having the formula
C.sub.13 H.sub.21 ClN.sub.2 O, is crystallized from ethanol and isopropyl
ether, and is readily soluble in water.
Local anesthetic drugs block nerve impulses by interfering with the opening
of voltage gated sodium channels of excitable membranes, such as neuronal
cell membranes. When enough channels are blocked, neuronal conduction is
terminated within the anesthetized portion of the particular nerve axon.
This mechanism of pain relief is quite different from those used by
analgesic agents.
The potency of anesthetics in clinical situations depends on both the
ability to reach the nerve fibers and their intrinsic blocking activities.
Factors such as nerve sheath penetration, vascular absorption, and local
tissue binding are all important determinants of functional potency. In
addition, volume, pH, and buffering capacity of the injected anesthetic
solution are important.
Local anesthetics are traditionally injected into the desired site of
action by the use of a needle and syringe. Most formulations of local
anesthetics are aqueous solutions of the hydrochloride salt forms of the
drug in 0.5-2% weight/volume concentrations. These solutions are designed
for injection either diffusely into tissue, around nerves, or into the
intrathecal or epidural spaces.
The delivery of local anesthetic agents to skin wounds remains a problem
and is largely still achieved by injection of the aqueous local anesthetic
around or into the wound. This treatment mechanism can be disadvantageous
because the needle itself causes pain on penetration, and, the volume of
anesthetic solution can cause stretching at the site, which also causes
pain. Furthermore, preservatives such as parabens, ethyl alcohol,
cetylpyridinium chloride, benzalkonium chloride, and the like, which may
be used in the aqueous solution can cause stinging at the wound site.
A topical formulation of 0.5% tetracaine hydrochloride, epinephrine 1:2000,
and 11.8% cocaine hydrocloride, is described in Handbook of Pediatric
Emergencies, 1994, Ed. Baldwin, Little, Brown and Company. This
formulation is applied by holding a cotton ball soaked in the solution for
a period of 10-15 minutes. This treatment scheme and formulation suffers
from the slow absorption of the salt form of the local anesthetic which
requires that the solution be held in place for long periods of time, the
use of cotton balls directly on the wound site, and the requirement of
cleaning the wound prior to application of the formulation. In addition,
in order to obtain deep blocking, the treatment scheme must be
supplemented with injection of a local anesthetic formulation.
Topical anesthesia requires rapid absorption of drug in order to block
nerve conduction. Topically applied gels and fluids have not proven
successful in many environments. For example, intraurethrally delivered
lidocaine gel was shown to be no more effective than plain lubricant jelly
during cystoscopy (see, Stein et al., Journal of Urology, June 1994, Vol.
151, pages 1518-1521).
Lidocaine has been delivered in aerosol form to the mucous membranes of the
airway using nebulized aqueous preparations of the lidocaine hydrochloride
salt and using metered dose inhaler (MDI) formulations with
chlorofiuorocarbon (CFC) propellants and solubilizing and/or dispersing
agents. However, experience has shown that these formulations suffer from
large droplet formation which prevents satisfactory inhalable or indirect
delivery to the upper airway, including the larynx and trachea. In
addition, the requirement of organic solvents and adjuvants in the aerosol
formulations limits the concentration of the active medicament, and thus
limits the dispensable dose. Moreover, these formulations have not been
used topically and would not be successful in topical application because
the adjuvants and solvents are themselves irritants which would cause pain
when administered to sensitive mucous membranes and wounds.
Chlorofiuorocarbon (CFC) propellants have been widely used in aerosol
formulations; however, CFC propellants are being phased out under
international treaties due to their possible adverse impact on the ozone
layer. Hydrofluorocarbon (HFC) propellants have been investigated
extensively as substitutes for CFCs. While chemically similar to to CFCs,
HFCs have some property differences that have made formulating certain
products very difficult, and particularly formulating medical and
pharmaceutical aerosols wherein the ability to provide a controlled amount
of drug and, in some instances, particles or droplets of respirable size
(e.g., less than 10 .mu.m), is extremely important.
SUMMARY OF THE INVENTION
An object of this invention is to provide novel aerosol formulations which
include prilocaine, with or without additional medicaments, in HFC
propellants, without additional organic solvents and surfactants.
Another object of this invention is to provide a method of using prilocaine
as a solubilizing agent in HFC propellants.
Another object of this invention is to provide a new composition of
prilocaine wherein prilocaine, in liquid or amorphous form, is associated
with an HFC propellant.
According to the invention, prilocaine in base form has been found to be
soluble in the HFC propellants 1,1,1,2-tetrafluoroethane and
1,1,1,2,3,3,3-heptafluoropropane. Prilocaine is soluble when combined with
the HFC propellant in liquid form, but is not soluble when combined with
the HFC propellant in its crystalline form. The combination of prilocaine
base in liquid form and HFC propellant forms a stable liquid solution
having an oily consistency. When prilocaine base in liquid form is mixed
with the HFC propellant it is thought to form a 1:1 molecular ionic
complex that keeps the prilocaine in solution and alters the solubility of
this complexed mixture such that it is completely miscible or soluble in
prilocaine. The prilocaine complexed HFC propellant has altered physical
characteristics with improved solubility, improved suspension
characteristics, a low vapor pressure and higher viscosity. The
association or complex between prilocaine and HFC propellants is disrupted
by the presence of water or ethanol resulting in the release of the HFC
propellant. Prilocaine liquid can be combined with other medicaments, and
particularly other anesthetics, and serve as a solubilizing agent by
improving the solubility characteristics of the HFC propellant such that
the added local anesthetic forms a stable solution in the prilocaine/HFC
solution complex. The oily character of the prilocaine liquid/HFC complex
may serve as a valve lubricating aid when dispensing the aerosol
formulation from an MDI; thereby, overcoming or obviating the conventional
formulations which need additional valve lubricants. The prilocaine
liquid/HFC complex also allows the creation of stable suspensions of
certain particulate medicaments (e.g., beta-agonists such as albuterol,
etc.). The liquid character of the prilocaine/HFC complex may be
advantageous in topical treatment methodologies since the prilocaine can
be sprayed onto a site to coat the site with a liquid, as opposed to a
fine powder, which will be more rapidly absorbed due to the liquid
character of the prilocaine, the fact that the prilocaine is present as a
lipid-soluble base, and the rapid departure of the complexed HFC
propellant from the interaction of the complex with water on the membrane
and skin surfaces of the patient.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION
Liquid prilocaine base can be made by suspending prilocaine hydrochloride
in ethyl acetate and washing with a suitable aqueous base, such as sodium
bicarbonate, until all the solid is consumed. The ethyl acetate can be
removed using standard rotary evaporation or other procedures. After
removal of ethyl acetate, the prilocaine base residue is then dissolved in
a lower boiling point solvent, such as dichloromethane, to remove the
ethyl acetate by azeotropic distillation. The dichloromethane is then
evaporated off using a rotary evaporator, and the prilocaine base is dried
under high vacuum.
The prilocaine base obtained by the above procedure was a liquid at room
temperature, but was easily converted to its usual crystalline needle form
by cooling or by the addition of crystal seeds to the liquid. As noted
above, prilocaine is ordinarily a solid at room temperature which has the
form of crystalline needles that melt at 38.degree. C. However, the
processing conditions used formed a liquid prilocaine base below its
normal melting point. This is not an unusual occurrence where a low
melting point solid is found to remain in liquid form below its melting
point; however, this property in prilocaine base has been heretofor
unknown. Further cooling or the addition of crystal seeds crystallizes
these substances and they remain in solid form up to their predicted
melting point.
A reference standard prilocaine base sample obtained from the Astra
Pharmaceutical Company of Sweden was used to verify the nature and purity
of the liquid prilocaine base as described above. It was confirmed using
thin layer chromatography on silica gel, infra-red (IR) spectrometry, and
nuclear magnetic resonance (NMR) imaging that the liquid prilocaine base
was the same as the standard prilocaine base.
It has been discovered that the liquid prilocaine base can be readily
solubilized or absorbed into HFC propellants 1,1,1,2-tetrafiuoroethane and
1,1,1,2,3,3,3-heptafluoropropane. The combination of liquid prilocaine
base and the HFC propellant forms a stable oily liquid.
By contrast, prilocaine base in its ordinary crystalline needle form is not
soluble in HFC propellants. The crystal structure is thought to prevent
the polar/ionic interaction of prilocaine and HFC propellant and the
crystals remain insoluble.
When the crystalline needles are melted by heating to a temperature above
38.degree. C., the liquid was found to be readily solubilized and absorbed
in the HFC propellants to form a stable oily liquid. As long as no needle
crystals are present, the prilocaine base/HFC combination remains stable
when cooled down to -82.degree. C.; however, seeding the solution with
needles will cause dissolution of the prilocaine base/HFC combination.
In addition to liquid prilocaine base being found to be soluble in HFCs, it
has been found that prilocedne base in micro rod crystal form, as opposed
to the usual needle form, is soluble in HFC propellants. Micro rods of
prilocaine base may be obtained using precipitation and filtering from a
super-saturated solution. The Reference Standard Sample of prilocaine base
from Astra Pharmaceuticals was provided in micro rod crystal form. The
micro rods are identical to the crystalline needles of prilocaine base
chemically, but not physically.
An important feature of this invention is that prilocaine base be used in
liquid form or micro-rod form when making aerosol formulations with HFC
propellants. Combining liquid or micro-rod prilocaine base with HFC
propellants produces a stable complex or association that has the form of
an oily liquid solution which can be used in MDIs or other formulations.
The solution is ideal for topical delivery to a wound site or the like, in
that the prilocaine base is applied as a liquid and is absorbed quickly,
absorption is enhanced by the prilocaine being present in its lipid
soluble base form, and the complexed HFC propellant quickly dissociates
from the prilocaine upon contact with water and other contaminants at the
site. The rapid absorption allows for quick and effective local anesthesia
without causing pain or discomfort on application. Because the prilocaine
base is in liquid form as it is sprayed, it has the utility of forming a
thin film coating on any site needing to be anesthetized. Such sites
include the mucous membranes of the airway, gastrointestinal tract and
genito-urinary tract, and all wound surfaces where the epidermis is
comprimised to allow rapid absorption of topical local anesthetic as well
as internal organ surfaces exposed during surgical procedures. The oily
character of the liquid improves asorption to the applied surface while
remaining easy to wash or wipe off.
Example 1 describes the formation of the complex of liquid prilocaine base
and HFC propellants.
EXAMPLE 1
Liquid prilocaine base, provided as an oily liquid without any crystal
seeds, is readily miscible with the hydrofluorocarbon propellants
1,1,1,2-tetrafiuoroethane (HFC-134a) and 1,1,1,2,3,3,3-heptafluoropropane
(HFC-227). Likewise, prilocaine base in micro rod crystalline form is
readily miscible with the hydrofluorocarbon propellants
1,1,1,2-tetrafiuoroethane (HFC-134a) and 1,1,1,2,3,3,3-heptafluoropropane
(HFC-227). The combination of the liquid prilocaine base or micro rod
prilocaine base and the HFC propellants forms a stable liquid solution.
During formulation of a particular prilocaine base/HFC solution, liquid
prilocaine was placed in a 4 ounce glass bottle of known weight. The
bottle was weighed to determine the weight of liquid prilocaine base. The
bottle was then sealed with a continuous valve. HFC-134a was added to the
bottle by pressure fill. The bottle was weighed again to determine the
weight of HFC-134a added. The bottle was agitated gently to ensure
intermingling of the liquid prilocaine base and the HFC. The mixture was
found to form a clear and stable solution that did not precipitate out the
prilocaine base when left standing or cooled. The valve was opened for
short intervals to let out vaporized HFC-134a gas, and the bottle was
weighed intermittently. The solution remained clear and stable after each
portion of HFC-134a gas was discharged. This process was continued until
all vaporizable gas was let out of the bottle. The weight of the bottle
after the vaporizable gas had been discharged indicated a 1:1 weight ratio
of prilocaine:HFC-134a residue (product remaining in bottle). By leaving
the bottle open for twenty-four hours with intermittent weighing, it was
determined that the HFC-134a slowly came out of solution until the weight
of the bottle indicated the presence of liquid prilocaine base alone.
Infra-red spectroscopy confirmed that the recovered liquid prilocaine base
was unaltered by the interaction with HFC-134a.
Cooling of a 1:1 mixture of prilocaine:HFC-134a prepared as described above
to -82.degree. C. did not result in prilocaine crystallizing out of
solution. Instead, the prilocaine:HFC-134a formed a more viscous solution.
This result is surprising in view of prilocaine oridinarily having a
38.degree. C. melting point, and the 1:1 solution being highly
concentrated, and it further suggests that some form of association or
complex (e.g., ionic) between liquid prilocaine base and the HFC is
created. Upon rewarming of the viscous oil to room temperature, the
prilocaine:HFC-134a remained a liquid. The cooling test described above
demonstrates that the liquid prilocaine base can be used in cold-filling
operations that are ordinarily used in MDI packaging or the like without
adverse consequences.
Seeding of the 1:1 solution with prilocaine base needle crystals resulted
in the prilocaine base crystallizing out of solution over several days.
The association of liquid prilocaine base with HFC propellants has been
found to allow its use as a solubilizing agent for dissolving and/or
dispersing other medicaments within HFC propellants. In particular,
prilocaine base can be used as a solubilizing aid for other local
anesthetics, most of which are not ordinarily soluble in HFC propellants.
For example, prilocaine base can be used in HFC propellants in combination
with the anesthetics procaine, cocaine, chloroprocaine, tetracaine,
mepivacaine, lidocaine, bupivacaine, etidiocaine, ropivacaine, and
benzocaine. Prilocaine may be used in the preparation of HFC aerosol
formulations that are used in inhalation (nasal and/or oral), and topical
delivery (e.g., skin wounds, hollow viscus and body cavity delivery), and
may be used to solubilize, disperse and/or form stable suspensions with
other medicaments including, for example, bronchodilators,
anti-inflammatories, antitussives, vasoactive drugs, vasoconstrictors,
antibiotics, peptides, steroids, enzymes, antihistamines, benzodiazepines,
anti-psychotics, sedatives, vitamins, hormones, enzyme and receptor
inhibitors and agonists, 5-aminolevulinic acid and similar agents,
antiseptics and disinfectants, etc.
Example 2 provides the compositions of several different HFC aerosol
formulations which have been prepared. It can be seen that prilocaine base
can be used at widely varying concentrations and may range from 1-99% by
weight of the aerosol formulation. Most preferably, the liquid prilocaine
base will constitute 1-60% by weight of the HFC aerosol formulation. The
HFC propellant can constitute 1-99% by weight of the aerosol formulation,
and most preferably 60% to 95% by weight of the aerosol formulation.
If an additional medicament is combined with prilocaine and the HFC
propellant, it can constitute 0.01-99% by weight of the aerosol
formulation, and most preferably 0.01 to 10% by weight of the aerosol
formulation.
EXAMPLE 2
Using the same general method of Example 1, the following formulations were
prepared and they provided stable solutions.
______________________________________
Formulation 1
Prilocaine base
140 mg 4.4% w/w
Lidocaine base 1260 mg 40.0% w/w
HFC-134a 1760 mg 55.6% w/w
Formulation 2
Prilocaine base
340 mg 15.5% w/w
Lidocaine base 1260 mg 57.7% w/w
HFC-134a 580 mg 26.6% w/w
Formulation 3
Prilocaine base
520 mg 34.9% w/w
Lidocaine base 1260 mg 84.7% w/w
HFC-134a 175 mg 11.7% w/w
Formulation 4
Prilocaine base
411 mg 33.4% w/w
Lidocaine base 476 mg 38.6% w/w
HFC-134a 344 mg 28.0% w/w
______________________________________
When cooled to -82.degree. C., formulations 1-4 experienced crystal
precipitation of the lidocaine base leaving a thick oily solution of
prilocaine and HFC-134a. The lidocaine crystals went back into solution
upon rewarming. When the bottle was left open for longer than 24 hours,
the HFC-134a evaporated and the local anesthetics crystallized when
cooled.
______________________________________
Formulation 5
Benzocaine base
322 mg 3.7% w/w
HFC-134a 8283 mg no solution
Formulation 6
Prilocaine base
184.6 mg 56.2% w/w
Benzocaine base
12.7 mg 3.8% w/w
HFC-134a 131.2 mg 40.0% w/w
clear solution
Formulation 7
Bupivacaine base
30.0 mg 0.3% w/w
HFC-134a 10000 mg no solution
Formulation 8
Bupivacaine base
166.0 mg 33.5% w/w
Prilocaine base
176.0 mg 35.5% w/w
HFC-134a 153.0 mg 31.0% w/w
clear solution
______________________________________
Formulations 4-8 show that ordinarily insoluble anesthetics (e.g.,
benzocaine and bupivacaine) can be solubilized in HFC propellants when the
liquid prilocaine base:HFC-134a solution is used. When cooled to
-82.degree. C., the benzocaine and bupivacaine precipitated out of
solution. Upon rewarming, the benzocaine and bupivacaine dissolved back
into solution.
______________________________________
Formulation 9
Tetracaine base
60 mg 1.9% w/w
HFC-134a 3000 mg 98.1% w/w
clear solution
maximum solubility of tetracaine
Formulation 10
Tetracaine base
150 mg 5.8% w/w
Prilocaine base
178 mg 6.9% w/w
HFC-134a 2250 mg 87.3% w/w
______________________________________
Formulations 9-10 demonstrate that prilocaine can be used to enhance the
solubility of certain medicaments in HFC propellants
______________________________________
Formulation 11
Phenylephrine base
6 mg 0.12% w/w
HFC-134a 4890 mg no solution
Formulation 12
Phenylephrine base
8 mg 0.2% w/w
Prilocaine base 993 mg 24.7% w/w
Lidocaine base 1009 mg 25.1% w/w
HFC-134a 1110 mg 50.0% w/w
______________________________________
The three medicament bases were first heated and dissolved together. This
formulation produced a stable suspension of the phenylephrine. No signs of
crystal growth were observed.
______________________________________
Formulation 13
Phenylephrine base
3 mg 0.2% w/w
Prilocaine base 402 mg 24.7% w/w
Bupivacaine base 409 mg 25.1% w/w
HFC-134a 814 mg 50.0% w/w
______________________________________
This formulation resulted in a stable suspension. Preheating and mixing of
the base compounds was not required in this formulation but is recommended
as a method of obtaining even particle sizes of phenylephrine in the
suspension.
Formulations 11-13 demonstrate the utility of prilocaine in acting as a
dispersing agent (as opposed to solubilizing agent) in forming a stable
suspension of a medicament.
While the invention has been described in terms of its preferred
embodiments, those skilled in the art will recognize that the invention
can be practiced with modification within the spirit and scope of the
appended claims.
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